There is now a considerable body of evidence suggesting that a major factor in the development of IDDM is a primary defect in the peripheral regulation of self-reactive T cells. The NOD mouse develops autoimmune diabetes spontaneously and is known to have a number of inherent immunoregulatory defects, one of which is deficient expression and function of the molecule, cytotoxic T lymphocyte antigen 4 (CTLA- 4/CD152) on T cells. CTLA-4 is a negative regulator of T cell activation and has been described as the molecule responsible for the initiation of T cell anergy in vivo. Previous work by our lab has shown that inhibition of CTLA-4 function, caused by treating non-autoimmune mice with anti- CTLA-4 antibody, leads to a dramatic increase in the T cell response to islet cell autoantigen. On the other hand, in diabetes-prone NOD mice, T cell responses to islet cell immunization are high to begin with and antibody treatment has little effect, one indication that CTLA-4 is not functioning well in the NOD.
The first aim i n this proposal is to determine whether peripheral tolerance can be broken in vivo via abrogation of CTLA-4 function in non-autoimmune mouse strains. In these experiments, we will attempt to define conditions under which immunization of non-diabetes-prone mice with islet cells as self-antigen will lead to development of diabetes. Under the second aim, we will determine whether blocking CTLA-4 function in non-autoimmune mice will allow for the, isolation of islet-specific T cells and whether those T cells have pathogenic properties. Islet-reactive T cell clones from nonautoimmune mice will be compared to a panel of NOD-derived diabetogenic T cell clones. These studies will allow us to determine how a breakdown in peripheral tolerance due to defective function of CTLA-4 contributes to the autoimmune environment that results in IDDM.
